# B. thuringiensis crystal proteins as powerful next-generation anthelmintics

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $719,185

## Abstract

New treatments are urgently needed for parasitic gastrointestinal nematodes (GINs; hookworms, whipworms,
roundworms) that infect ~1.5 billion people and cause significant morbidity in children, pregnant women, and
working adults. Mass drug administration with albendazole has not been curative, and there are limitations
with additional approaches involving ivermectin and the experiment drug emodepside. Controlling GINs
remains a critical unmet medical need. For over 60 years, Bacillus thuringiensis crystal (Cry) proteins have
been safely and massively used to combat insect pests that vector disease and damage crops. Pioneering work
has shown that some Cry proteins (e.g., Cry5Ba) target nematodes and are anthelmintics. Orally administered
Cry5Ba is highly effective against GINs in rodents, dogs, sheep, pigs, and horses and against all three major
human GIN classes. The goal here is to develop Cry protein anthelmintics to meet World Health Organization
(WHO) Target Product Profiles (TPPs) for GIN anthelmintics and perform key studies leading to first in human
trials. Anthelmintic Cry proteins can be delivered via a simple-to-produce, inexpensive, safe, and a scalable
form of anthelmintic Cry protein called IBaCC for Inactivated Bacteria with Cytosolic Crystal(s). Currently, six
Cry proteins are known anthelmintics. The means to study all three GIN classes in rodents, to measure synergy
of Cry protein combinations, to produce hybrid (domain swapped) Cry proteins with increased activity, and to
produce IBaCC in commercially relevant yields via industry collaborators are successfully in hand. These
advancements will be leveraged here to engineer Cry protein therapies to meet the WHO's TPP to target all
three GIN classes with high efficacy, low dose, and low cost and to advance Cry protein anthelmintics to the
clinic. In Aim 1, it is hypothesized that the WHO TPP will be achieved by identifying synergy among all pairwise
combinations of six anthelmintic Cry proteins in vitro against all three classes of GINs. All synergistic
combinations will be tested in vivo in rodents against all three GIN classes at a Step 1 TPP of 5 mg/kg. Fit for
purpose formulation strategies for improved gastric resistance and anthelmintic efficacy in rodent models vs.
the three GINs will also be tested in this aim. In Aim 2, it is hypothesized that the WHO TPP will be achieved
by swapping domains among the six anthelmintic Cry proteins to generate hybrid Cry proteins. These hybrid
proteins will be tested in vitro against all three GIN classes for superior efficacy and then in vivo in rodents
against all three GIN classes at the Step 1 TPP. Combining Cry proteins (1) and swapping domains among Cry
proteins (2) are evolutionary strategies seen in nature to increase Cry protein efficacy and spectrum of activity.
In Aim 3, the best Cry protein combinations will be tested against multi-drug-resistant dog hookworms in vitro
and in vivo in order to select a single lead candidate for G...

## Key facts

- **NIH application ID:** 10981674
- **Project number:** 2R01AI056189-20A1
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** RAFFI V AROIAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $719,185
- **Award type:** 2
- **Project period:** 2005-04-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981674

## Citation

> US National Institutes of Health, RePORTER application 10981674, B. thuringiensis crystal proteins as powerful next-generation anthelmintics (2R01AI056189-20A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10981674. Licensed CC0.

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